Research update: New treatment could reduce brain damage from stroke, and more

NR Times explores the latest developments in the world of neuro-rehabilitation.

Study of killifish reveals how protein dysfunction develops in vertebrate brain cells, shedding light on cognitive decline

A new study has shed light on diseases like Alzheimer’s, Parkinson’s, and ALS.

Ageing and neurodegeneration are both known to disrupt the production of functional proteins in cells – a process called “proteostasis,” or protein homeostasis.

Brain cells in particular fall prey to proteostasis disruptions, which are linked to the accumulation of protein aggregates in neurodegenerative diseases.

In a new study, Stanford researchers have discovered the cascade of events that leads to declining proteostasis in aging brains.

The findings, based on study of the turquoise killifish, lay the foundation for developing therapies that can combat and prevent neurodegenerative diseases in people – and the gradual decline in mental abilities we will all face one day.

The turquoise killifish develop many issues as they grow old and provide a great model of accelerated ageing. Studying why and how the brain ages would be harder in longer-lived animals, such as mice.

To make their new discovery, the researchers conducted a comprehensive investigation of proteostasis in the brains of aging killifish.

The scientists compared young, adult, and old killifish. They looked at various players in protein production, such as amino acid concentrations, levels of transfer RNA, messenger RNA (mRNA), proteins, and more.

In cells, proteostasis balances protein synthesis and degradation and also prevents protein aggregation – harmful clumps of proteins that can result from errors in protein folding.

Proteostasis dysfunction and aggregation are part of a series of molecular and cellular changes classified as ageing hallmarks.

Proteostasis has received attention as a likely link between brain ageing and neurodegenerative diseases tied to protein aggregation, like Alzheimer’s.

Frydman’s lab explores how cells achieve proteostasis and has previously focused on how aging affects proteostasis in the simple models of aging provided by yeast and roundworms.

The new study confirms that ageing processes observed in those simple organisms reflect those in more complex vertebrates like killifish – and humans.

Ultimately, the team located the disruption at a specific stage of protein synthesis called translation elongation. In this step, the ribosome enacts its role as the cellular machinery responsible for converting mRNA into proteins by moving along the mRNA and adding amino acids one by one.

In the ageing fish brains, the researchers documented ribosomes colliding and stalling, which both resulted in reduced levels of proteins and protein aggregation.

The researchers say that the results show that changes in the speed of ribosome movement along the mRNA can have a profound impact on protein homeostasis, and highlight the essential nature of ‘regulated’ translation elongation speed of different mRNAs in the context of ageing.

The finding helped to illuminate another ageing mystery.

One of the hallmarks of ageing in all organisms, including humans, is called “protein-transcript decoupling.” In this phenomenon, changes in levels of some mRNA no longer correlate to changes in protein levels in aged individuals.

The new study shows that changes in protein synthesis during ageing, including ribosomes, can explain the “protein-transcript decoupling.”

Since many of the affected proteins are involved in genome maintenance and integrity, these new observations rationalise why these processes decline during ageing.

Study author Judith Frydman is the Donald Kennedy chair in the School of Humanities and Sciences at Stanford.

The researcher said: “Showing that the process of protein production loses fidelity with aging provides a kind of underlying rationale for why all these other processes start to malfunction with age.

“And, of course, the key to solving a problem is to understand why it’s gone wrong. Otherwise, you’re just fumbling in the dark.”

As a next step, the researchers will explore directly how ribosome dysfunction – which they identified as a key culprit of declining proteostasis – may contribute to age-related neurodegenerative disorders in people.

They also want to know whether targeting translation efficiency or ribosome quality control in treatments can restore proteostasis in brain cells and even delay ageing-related cognitive decline.

Dementia takes 3.5 years to diagnose after symptoms begin

People with dementia are diagnosed an average of 3.5 years after symptoms are first noticed, or even longer (4.1 years) for those with early-onset dementia, a new study has found.

The researchers reviewed data from 13 previously published studies which took place in Europe, US, Australia and China, reporting data on 30,257 participants.

The research team was investigating the average interval between symptom onset to the final diagnosis of dementia.

They found that younger age at onset and having frontotemporal dementia were both linked to longer time to diagnosis.

While data on racial disparities was limited, one of the studies reviewed found that black patients tended to experience a longer delay before diagnosis.

Lead author Dr Vasiliki Orgeta, UCL Division of Psychiatry, said: “To speed up dementia diagnosis, we need action on multiple fronts.

“Public awareness campaigns can help improve understanding of early symptoms and reduce stigma, encouraging people to seek help sooner.

“Clinician training is critical to improve early recognition and referral, along with access to early intervention and individualised support so that people with dementia and their families can get the help they need.”

New treatment could reduce brain damage from stroke

Cambridge scientists have developed and tested a new drug in mice that has the potential to reduce damage to the brain when blood flow is restored following a stroke.

As many as one in four people will have a stroke during their lifetime.

The first few hours following a stroke are crucial – the blood clot needs to be removed quickly so that the oxygen supply to the brain can be restored; otherwise, the brain tissue begins to die.

Currently, the outcome for stroke patients receiving even the best available treatment, known as mechanical thrombectomy, is still poor, with fewer than one in 10 patients leaving hospital with no neurological impairment.

Mechanical thrombectomy is a minimally invasive medical procedure involving the insertion of a thin tube, known as a catheter, into a blood vessel, often through the groin or arm.

This is guided to the blood clot, where it is removed by a tiny device, restoring normal blood flow.

Restoring blood flow too suddenly can make things worse, however. This is called ischaemia-reperfusion injury.

When blood rushes back into the oxygen-starved tissue (a process known as reperfusion), the damaged cells struggle to cope, leading to the production of harmful molecules called free radicals that can damage cells, proteins, and DNA. This triggers further damage and can cause an inflammatory response.

The Cambridge team has previously shown that when the brain is starved of oxygen, a build-up occurs of a chemical called succinate.

When blood flow is restored, the succinate is rapidly oxidised to drive free radical production within mitochondria, the ‘batteries’ that power our cells, initiating the extra damage.

This occurs within the first few minutes of reperfusion, but the researchers showed that the oxidation of succinate can be blocked by the molecule malonate.

Professor Mike Murphy from the Medical Research Council Mitochondrial Biology Unit said: “We discovered in our labs that we can get malonate into cells very quickly by lowering the pH a little, making it a bit more acidic, so that it can cross the blood-brain barrier better.

“If we inject it into the brain just as we’re ready to reperfuse, then we can potentially prevent further damage.”

In a study, the team has shown that treating the brain with a form of the chemical known as acidified disodium malonate (aDSM) alongside mechanical thrombectomy greatly decreased the amount of brain damage that occurs from ischaemia-reperfusion injury by as much as 60 per cent.

The researchers say that this approach reduces the amount of dead brain tissue resulting from a stroke.

Mechanical thrombectomy is increasingly used in the NHS, and the researchers hope that with the addition of aDSM as a treatment alongside this intervention, they will be able to improve outcomes significantly when the procedure is more widely adopted.

Improving human memory, movement and quality of life

The brains’ cerebellum could hold the key to preserving memory, movement and quality of life as we age.

Located at the back of the head, the cerebellum coordinates voluntary movements, posture, balance and is associated with cognitive functions such as memory and language.

Normal functioning is disrupted when healthy nerve cells in the cerebellum stop working, lose connections with other brain cells or die.

Dr. Jessica Bernard is asking questions about how the brain changes over time and whether we can develop interventions to slow or mitigate the negative effects of these changes.

In a two-year research study, Bernard is collecting data from 120 participants evenly segmented into three groups: young healthy adults, cognitive normal older adults and older adults with some level of mild cognitive impairment.

Cognitive and motor behaviors are inextricably linked and can impact an individual’s ability to perform the basic activities of daily living (ADL) including bathing, dressing, toileting, transferring (unassisted movement between a chair or bed), continence and feeding.

The aim of the study is to improve outcomes for both groups of older adults through a non-invasive therapeutic approach using Theta burst simulation (TBS).

Success would in part be gauged by participant’s enhanced abilities to accomplish ADL and maintain independent living as long as possible.

TBS is a type of transcranial magnetic stimulation that uses short magnetic pulses to stimulate the brain by matching the brain’s natural theta rhythms.

Bernard believes TBS may influence behavioral performance, function activation and network connectivity in individuals with either a healthy ageing decline or mild cognitive impairment.

Bernard’s research is advancing brain science, and positive results in this study could lead to TBS being used to treat more severe types of progressive brain disorders.